Agent No Help in Brain Trauma

Action Points

Explain that the COBRIT randomized, placebo-controlled trial found no improvement in outcomes for patients receiving citicoline for traumatic brain injury compared with placebo.

Note that there were no differences in outcome depending upon the severity of the brain injury either.

Citicoline -- a chemical that occurs naturally in the body and is available in the U.S. as a nutraceutical -- did not improve outcomes among patients with traumatic brain injury, the randomized COBRIT trial showed.

Functional and cognitive outcomes assessed with a battery of tests 90 days after the injury were not significantly different between the patients who received citicoline and those who received placebo, according to Ross Zafonte, DO, of Harvard Medical School in Boston, and colleagues.

There were also no differences in any secondary outcome, including survival, the researchers reported in the Nov. 21 issue of the Journal of the American Medical Association.

The findings call into question the use of citicoline around the world, they said.

The agent is approved for use in patients with traumatic brain injuries in 59 countries. Preclinical studies and some small clinical trials have suggested that citicoline has potential neuroprotective effects and may enhance neurological repair after a brain injury, but most randomized trials in patients with traumatic brain injury have failed to show any benefit.

"The absence of an effect in prior trials and in COBRIT may be attributable either to the therapy simply being ineffective or to the heterogeneous pathophysiological nature of traumatic brain injury," Zafonte and colleagues wrote. "This would suggest that the mechanisms of action of drugs used in future ... trials would need to be tested in specific subtypes of traumatic brain injury, where they are likely to have a positive effect."

The COBRIT trial was a phase III, double-blind, randomized trial that included 1,213 patients treated at one of eight U.S. level 1 trauma centers for a nonpenetrating traumatic brain injury. The seriousness of the injuries ranged from complicated mild traumatic brain injury to severe injury.

The patients received either daily enteral or oral citicoline 2,000 mg or matching placebo starting within 24 hours of the injury.

The primary outcome was a global measure of functional and cognitive status -- the TBI Clinical Trials Network Core Battery, which includes nine scales -- at 90 days.

The trial was stopped for futility at the fourth interim analysis. The primary outcome was no different between the citicoline and placebo groups at 90 days (OR 0.98, 95% CI 0.83 to 1.15). The severity of injury did not affect the results.

The rate of a favorable outcome for each of the nine scales of the assessment ranged from 35.4% to 86.5% in the citicoline group and from 35.6% to 84% in the placebo group, with no between-group differences.

In an accompanying editorial, Robert Ruff, MD, PhD, and Ronald Riechers II, MD, of the Cleveland VA Medical Center, noted that among the possible reasons citicoline did not improve outcomes was the fact that there are many different mechanisms of injury involved in brain trauma.

"Hence, optimal treatment ... may require that multiple agents and modalities be used to address all of the regional and widespread injury processes that occur in traumatic brain injury," they wrote.

The study was supported by grants from the National Institute of Child Health and Human Development at the following institutions: Temple University; University of Alabama at Birmingham; University of Maryland; University of Pittsburgh; University of Tennessee Health Sciences Center; University of Texas Southwestern; University of Washington; Virginia Commonwealth University; and Columbia University. Ferrer Grupo provided the citicoline and identical placebo used in the study.

The study authors and the editorialists reported that they had no conflicts of interest.

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